U.S. Pat. No. 4,083,985 describes a range of fused-ring quinuclidines which are described as psychomotor stimulators, and which may be regarded structurally as a quinuclidine nucleus fused to a cyclohexanone, cyclohexenone or delta-lactone moiety. These compounds are stated to be useful for treating (inter alia) Parkinsons' Disease and depression, and evidently possess anticholinergic activity. There is no indication in this Patent that any of these compounds possess cholinergic activity.
U.S. Pat. No. 4,104,397 describes spiro(1,3-dioxolane-4,3')quinuclidines which may have one or two alkyl and/or aryl substituents in the 2-position of the dioxolane ring. The Patent specifically describes the monomethyl, dimethyl and diphenyl compounds. The monomethyl compound is shown to have cholinergic activity and the diphenyl compound to have anticholinergic activity. The nature of the pharmacological activity exhibited by the other compounds embraced by this Patent is not described therein.
A chronic deficiency in vivo in central cholinergic function, that is to say in the function of acetylcholine as a neurotransmitter, has been implicated in a variety of neurologic and psychiatric disorders, including senile dementia of Alzheimer's type(SDAT), tardive dyskinesia, Pick's disease, Huntington's chorea, Gilles de la Tourette disease, Friedrich's ataxia, and Down's syndrome. Clinical data indicate that cholinergic transmission may have been compromised in persons affected with these diseases (Fisher and Hanin, Life Sciences, 27: 1615, 1980).
Among these disorders, SDAT is the most widespread neuropsychiatric disease (for reviews see Schneck et al, Am. J. Psychiatry, 139: 165, 1982 and Coyle et al, Science 219: 1184, 1983). The development of an effective treatment for SDAT is one of the most pressing needs facing medicine today. This age-related disease is becoming increasingly prevalent as the population of the elderly grows in line with the progressively higher life expectancy of the older population.
SDAT is characterized morphologically by an increased number of senile plaques in selected brain areas; biochemically by a significant reduction in presynaptic cholinergic markers in the same brain areas, the cortex and the hippocampus in particular; and behaviorally by a loss of cognitive functions in individual patients.
Since SDAT appears to be associated with brain cholinergic hypofunction, trials have been conducted in which ACh precursors (choline or lecithin), acetylcholinesterase inhibitors (physostigmine or tetrahydroaminoacridine) or direct acting muscarinic agonists (arecoline) have been administered to SDAT patients because of the ability of these agents to elevate, and thus presumably restore cholinergic activity in the brain. To date, the results have not been conclusive as to the efficacy of treatment with the above-mentioned agents; this is due mainly to unwanted side-effects, narrow therapeutic window, or lack of therapeutic efficacy.
There is an urgent need for drugs which are effective in the treatment of SDAT. Progress in this area has been hindered by the lack of adequate animal models that can mimic directly the cholinergic abnormality implicated in SDAT, and by a dearth of long-acting central cholinergic agonists which can discriminate among subclasses of receptors, and primarily activate those that are involved in cognitive functions. Most known cholinergic agonists (muscarinic drugs) have undesirable side-effects. A long-lasting, centrally active cholinomimetic drug without peripheral side effects would therefore be most useful. The R & D of such drugs would require their evaluation in suitable animals models for SDAT.
In this context, we have recently developed a selective presynaptic cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), which on intracerebroventricular injection in rats induces persistent cholinergic hypofunction that mimics the cortical and hippocampal cholinergic deficiency and the cognitive impairments reported in SDAT. This animal model could be extremely useful in developing novel treatment approaches for SDAT. (Fisher et al in Behavorial Models and the Analysis of Drug Action, eds. Spiegelstein and Levy, Elsevier, Amsterdam, 1983, p. 333; Fisher and Hanin, Ann. Rev. Pharmacol. Toxicol., 26: 161-81 (1986).
The availability of centrally active muscarinic compounds which have long acting central cholinergic activity without significant peripheral adverse side-effects capable of reversing cognitive impairments induced by AF64A in rats, could be extremely useful in treating SDAT and the above-mentioned related disease states.
Therapeutically active oxathiolane compounds and their pharmacology are relatively little known. Moreover, the literature is replete with unsuccessful attempts to replace a particular atom or group in a pharmacologically active chemical compound by a supposedly analogous atom or group, in an attempt to improve the therapeutic profile of the original compound. Thus, in replacing for example an oxygen-atom by a sulfur atom which has twice the atomic mass of oxygen, the result in pharmacological terms cannot be predicted with any degree of certainty.
However, we have now surprisingly discovered, and this discovery forms the basis of the present invention, that if in the spiro(dioxolane)quinuclidines of U.S. Pat. No. 4,104,397, the oxygen atom of the dioxolane ring which is more remote from the quinuclidine nucleus is replaced by a sulfur atom, and at the same time the ambit of the substituents at the 2-position is extended to include diarylmethylol, and alkyl substituted by aryl, then (i) the most active isomer of the monomethyl compound, while possessing a not dissimilar activity (measured by the Guinea-pig ileum induced contraction and muscarinic receptor binding tests) as compared with that of the most active isomer of the analogue disclosed in the aforementioned U.S. Patent, however exhibits significantly less pronounced side-effects (sialogenic and tremorigenic activity) than the latter compound under similar conditions; and (ii) the most active isomer of the monomethyl compound has interesting potential for the treatment of SDAT as shown by the tests on animal models mentioned above.
On the other hand, the vast majority of the other 2-substituted members of the series containing the sulfur atom in place of oxygen as aforesaid, and in particular those members containing at least one 2-substituent which is alkyl having three or more carbon atoms, cyclopentyl, cyclohexyl, aryl, diarylmethylol or alkyl substituted by aryl, have anticholinergic activity, as contrasted with the cholinergic activity of the monomethyl compound.